US20110177999A1 - Therapeutic Combinations Useful in Treating CFTR Related Diseases - Google Patents

Therapeutic Combinations Useful in Treating CFTR Related Diseases Download PDF

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US20110177999A1
US20110177999A1 US12/672,664 US67266408A US2011177999A1 US 20110177999 A1 US20110177999 A1 US 20110177999A1 US 67266408 A US67266408 A US 67266408A US 2011177999 A1 US2011177999 A1 US 2011177999A1
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oxo
carboxamide
quinoline
phenyl
cftr
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Ashvani Singh
Jennings Franklin Worley
Gregor Zlokamik
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Assigned to VERTEX PHARMACEUTICALS INCORPORATED reassignment VERTEX PHARMACEUTICALS INCORPORATED CORRECTIVE ASSIGNMENT TO CORRECT THE DATE OF THE INTERNATIONAL PATENT APP. WHICH WAS FILED ON AUGUST 7, 2008. PREVIOUSLY RECORDED ON REEL 021563 FRAME 0338. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT OF ASSIGNOR(S)INTEREST.. Assignors: WORLEY, JENNINGS FRANKLIN, III, ZLOKARNIK, GREGOR, SINGH, ASHVANI
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to therapeutic combinations and kits useful in treating CFTR-related diseases, such as cystic fibrosis.
  • ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions.
  • ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multidrug resistance proteins (like the MDR1-P glycoprotein, or the multidrug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function.
  • ABC transporters regulate a variety of important physiological roles within the body and provide defense against harmful environmental compounds. Because of this, they represent important potential drug targets for the treatment of diseases associated with defects in the transporter, prevention of drug transport out of the target cell, and intervention in other diseases in which modulation of ABC transporter activity may be beneficial.
  • CFTR cAMP/ATP-mediated anion channel
  • CFTR is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue.
  • CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
  • CFTR cystic fibrosis
  • a defect in this gene causes mutations in CFTR resulting in cystic fibrosis (“CF”), the most common fatal genetic disease in humans. Cystic fibrosis affects approximately one in every 2,500 infants in the United States. Within the general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.
  • CF cystic fibrosis
  • CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport.
  • anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients.
  • CF patients In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death.
  • the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis.
  • individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea—perhaps explaining the relatively high frequency of the CF gene within the population.
  • the most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as ⁇ F508-CFTR. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.
  • deletion of residue 508 in ⁇ F508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727).
  • CFTR transports a variety of molecules in addition to anions
  • this role represents one element in an important mechanism of transporting ions and water across the epithelium.
  • the other elements include the epithelial Na + channel, ENaC, Na + /2Cl ⁇ K + co-transporter, Na + —K + -ATPase pump and the basolateral membrane K + channels, that are responsible for the uptake of chloride into the cell.
  • Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na + —K + -ATPase pump and Cl ⁇ channels expressed on the basolateral surface of the cell.
  • Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl ⁇ channels, resulting in a vectorial transport.
  • COPD chronic obstructive pulmonary disease
  • COPD dry eye disease
  • Sjögren's Syndrome a chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • CFTR dry eye disease
  • Sjögren's Syndrome a chronic obstructive pulmonary disease
  • COPD is characterized by airflow limitation that is progressive and not fully reversible. The airflow limitation is due to mucus hypersecretion, emphysema, and bronchiolitis.
  • Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD.
  • CFTR Dry eye disease
  • tear aqueous production and abnormal tear film lipid, protein and mucin profiles There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and diseases, such as cystic fibrosis and Sjögrens's syndrome.
  • Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration.
  • Sjögrens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis. Defective protein trafficking is believed to cause the disease, for which treatment options are limited. Modulators of CFTR activity may hydrate the various organs afflicted by the disease and help to elevate the associated symptoms.
  • CFTR cystic fibrosis caused by mutations in CFTR.
  • the activity of residual mutated CFTR in the membrane is enhanced using modulators (“Potentiators”) that increase the gating activity of the mutated CFTR in the membrane.
  • the number of mutated CFTR in the membrane is increased using, thereby enhancing the CFTR activity in the membrane. This increase, or “Correction”, is believed to be the result of correcting the misfolding of the CFTR protein, which, in turn, would lead to enhanced trafficking to the membrane. Compounds that Correct such trafficking are called “Correctors”. Because of the complementary nature of these two approaches, a combination therapy employing these two approaches affords a potent method to treat diseases such as cystic fibrosis.
  • the diseases associated with the first class of ER malfunction are cystic fibrosis, hereditary emphysema (due to a1-antitrypsin; non Piz variants), hereditary hemochromatosis, hoagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, Mucopolysaccharidoses (due to lysosomal processing enzymes), Sandhof/Tay-Sachs (due to ⁇ -hexosaminidase), Crigler-Najjar type II (due to UDP-glucuronyl-sialyc-transferase), polyendocrinopathy/hyperinsulemia, Diabetes mellitus (du
  • Glycanosis CDG type 1 hereditary emphysema (due to ⁇ 1-Antitrypsin (PiZ variant), congenital hyperthyroidism, osteogenesis imperfecta (due to Type I, II, IV procollagen), hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency (due to ⁇ 1-antichymotrypsin), Diabetes insipidus (DI), neurophyseal DI (due to vasopvessin hormone/V2-receptor), neprogenic DI (due to aquaporin Charcot-Marie Tooth syndrome (due to peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to ⁇ APP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's
  • CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport.
  • the mechanism involves elevation of cAMP and stimulation of CFTR.
  • Diarrhea is both a significant factor in malnutrition and the leading cause of death (5,000,000 deaths/year) in children less than five years old.
  • Diarrhea in barn animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as scours, is a major cause of death in these animals. Diarrhea can result from any major transition, such as weaning or physical movement, as well as in response to a variety of bacterial or viral infections and generally occurs within the first few hours of the animal's life.
  • ETEC enterotoxogenic E. coli
  • Common viral causes of diarrhea include rotavirus and coronavirus.
  • Other infectious agents include cryptosporidium, giardia lamblia , and salmonella , among others.
  • Symptoms of rotaviral infection include excretion of watery feces, dehydration and weakness. Coronavirus causes a more severe illness in the newborn animals, and has a higher mortality rate than rotaviral infection. Often, however, a young animal may be infected with more than one virus or with a combination of viral and bacterial microorganisms at one time. This dramatically increases the severity of the disease.
  • the present invention provides Corrector compounds pharmaceutically acceptable compositions thereof useful for treating or lessening the severity of a variety of CFTR-mediated diseases.
  • the present invention also provides therapeutic combinations of Correctors and Potentiators useful in treating CFTR-mediated diseases.
  • the present invention also provides therapeutic combinations of Correctors and Potentiators useful in treating diseases including, but not limited to, cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congen
  • the present invention relates to compounds that act as Correctors of CFTR and thus are useful in treating CFTR-mediated diseases.
  • the present invention also relates to combinations of Correctors of the present invention and a Potentiator.
  • Exemplary Potentiators are disclosed below in Table 2; the compounds of Table 2 are previously in disclosed in WO 2006002421.
  • the present invention relates to the use of Prazosin hydrochloride (1) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Prazosin hydrochloride and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient in need thereof.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Ivermectin (2) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Ivermectin and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Ivermectin and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Mibefradil hydrochloride (3) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Mibefradil hydrochloride and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Mibefradil hydrochloride and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Thioridazine (4) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Thioridazine and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Thioridazine and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Chlorpromazine hydrochloride (5) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Chlorpromazine hydrochloride and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Chlorpromazine hydrochloride and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Prochlorperazine maleate (6) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Prochlorperazine maleate and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Prochlorperazine maleate and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Perphenazine (7) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Perphenazine and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Perphenazine and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Amoxapine (8) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Amoxapine and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Amoxapine and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Clomiphene Citrate (9) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Clomiphene Citrate and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Clomiphene Citrate and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Amiodarone (10) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Amiodarone and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Amiodarone and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Desloratadine (11) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Desloratadine and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Desloratadine and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Promethazine hydrochloride (12) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Promethazine hydrochloride and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Promethazine hydrochloride and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Protriptyline hydrochloride (13) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Protriptyline hydrochloride and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Protriptyline hydrochloride and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Gefitinib (14) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Gefitinib and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Gefitinib and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Bepridil (15) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Bepridil and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Bepridil and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Itraconazole (16) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Itraconazole and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Itraconazole and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Oxyphenbutazone (17) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Oxyphenbutazone and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Oxyphenbutazone and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Clemastine fumarate (18) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Clemastine fumarate and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Clemastine fumarate and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Mefloquine Hydrochloride (19) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Mefloquine Hydrochloride and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Mefloquine Hydrochloride and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Thioguanine (20) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Thioguanine and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Thioguanine and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Paroxetine Hydrochloride Hemihydrate (21) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Paroxetine Hydrochloride Hemihydrate and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Paroxetine Hydrochloride Hemihydrate and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Vinpocetine (22) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Vinpocetine and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Vinpocetine and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Trimeprazine Tartrate (23) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Trimeprazine Tartrate and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Trimeprazine Tartrate and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Chlorimipramine hydrochloride (24) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Chlorimipramine hydrochloride and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Chlorimipramine hydrochloride and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Diphenoxylate Hydrochloride (25) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Diphenoxylate Hydrochloride and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Diphenoxylate Hydrochloride and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Amlodipine besylate (26) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Amlodipine besylate and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Amlodipine besylate and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Cyproheptadine hydrochloride (27) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Cyproheptadine hydrochloride and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Cyproheptadine hydrochloride and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Budesonide (28) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Budesonide and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Budesonide and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Ezetimibe (29) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Ezetimibe and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Ezetimibe and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Nitazoxanide (30) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Nitazoxanide and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Nitazoxanide and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Nelfinavir Mesylate (31) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Nelfinavir Mesylate and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Nelfinavir Mesylate and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Carvedilol (32) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Carvedilol and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Carvedilol and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Nortriptyline hydrochloride (33) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Nortriptyline hydrochloride and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Nortriptyline hydrochloride and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Loratadine (34) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Loratadine and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Loratadine and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Methylprednisolone (35) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Methylprednisolone and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Methylprednisolone and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Saquinavir (36) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Saquinavir and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Saquinavir and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Nicardipine hydrochloride (37) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Nicardipine hydrochloride and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Nicardipine hydrochloride and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Levothyroxine sodium (38) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Levothyroxine sodium and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Levothyroxine sodium and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Mirtazapine (39) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Mirtazapine and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Mirtazapine and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Cyclosporin A (40) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Cyclosporin A and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Cyclosporin A and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of Fluvastatin sodium (41) to correct the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising Fluvastatin sodium and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Fluvastatin sodium and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the present invention relates to the use of 34542-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid (42) to modulate the activity of mutant CFTR.
  • the present invention provides a therapeutic combination comprising 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid and a compound selected from Table 2.
  • the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid and a compound selected from Table 2.
  • said compound from Table 2 is compound 433.
  • the compounds of Table 1 are known drugs commercially marketed. One of skill in the art would be well aware of methods of making compounds of Table 1.
  • therapeutic combination means a combination of two or more therapeutic compounds either (i) administered to a patient in need thereof simultaneously in separate formulations or in a single formulation; or (ii) administered to a patient in need thereof at different timepoints as part of a regimen.
  • CFTR-mediated disases means a disease selected from cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysacchari doses, Sandhof/Tay-Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism
  • the present invention provides compounds that are useful as modulators of CFTR and thus are useful in the treatment of disease, disorders or conditions such as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidis
  • compositions comprising any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • a pharmaceutically acceptable derivative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
  • the present invention provides a method of treating a condition, disease, or disorder implicated by ABC transporter activity, e.g., CFTR.
  • the present invention provides a method of treating a condition, disease, or disorder implicated by a deficiency of the ABC transporter activity, the method comprising administering a composition comprising a compound selected from Table 1 to a subject, preferably a mammal, in need thereof.
  • the present invention provides a method of treating cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT
  • the present invention provides a method of treating cystic fibrosis comprising the step of administering to said patient a composition comprising a compound of the present invention.
  • an “effective amount” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoprotenemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidis
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, con
  • the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in a patient.
  • the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia.
  • the presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary Cl ⁇ concentrations, or ex vivo biochemical or histochemical techniques to monitor cell surface density. Using such methods, residual CFTR activity can be readily detected in patients heterozygous or homozygous for a variety of different mutations, including patients homozygous or heterozygous for the most common mutation, ⁇ F508.
  • the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients who have residual CFTR activity induced or augmented using pharmacological methods or gene therapy.
  • Such methods increase the amount of CFTR present at the cell surface, thereby inducing a hitherto absent CFTR activity in a patient or augmenting the existing level of residual CFTR activity in a patient.
  • the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients within certain genotypes exhibiting residual CFTR activity, e.g., class III mutations (impaired regulation or gating), class IV mutations (altered conductance), or class V mutations (reduced synthesis) (Lee R. Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV, and V cystic fibrosis Tansmembrane Conductance Regulator Defects and Opportunities of Therapy ; Current Opinion in Pulmonary Medicine 6:521-529, 2000).
  • Other patient genotypes that exhibit residual CFTR activity include patients homozygous for one of these classes or heterozygous with any other class of mutations, including class I mutations, class II mutations, or a mutation that lacks classification.
  • the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients within certain clinical phenotypes, e.g., a moderate to mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia.
  • phenotypes include patients exhibiting pancreatic sufficiency or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microcmulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as, for example, water or other solvents, solubil
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention are useful as modulators of CFTR.
  • the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of CFTR is implicated in the disease, condition, or disorder.
  • hyperactivity or inactivity of an ABC transporter is implicated in a particular disease, condition, or disorder
  • the disease, condition, or disorder may also be referred to as a “ABC transporter-mediated disease, condition or disorder”.
  • the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of an ABC transporter is implicated in the disease state.
  • the activity of a compound utilized in this invention as a modulator of an ABC transporter may be assayed according to methods described generally in the art and in the Examples herein.
  • the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as “appropriate for the disease, or condition, being treated”.
  • the additional agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound of the present invention, or a nutritional agent.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the present invention in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • the present invention provides a kit comprising:
  • said compound selected from Table 2 is compound 433.
  • said instructions in said kit comprises instructions for using said pharmaceutical composition comprising a compound selected from Table 1 and said pharmaceutical composition comprising a compound selected from Table 2.
  • Another aspect of the invention relates to modulating CFTR activity in a biological sample or a patient (e.g., in vitro or in vivo), which method comprises administering to the patient, or contacting said biological sample with a compound selected from Table 1 or a composition comprising said compound.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Modulation of CFTR in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of ABC transporters in biological and pathological phenomena; and the comparative evaluation of new modulators of CFTR.
  • a method of modulating activity of an anion channel in vitro or in vivo comprising the step of contacting said channel with a compound selected from Table 1.
  • the anion channel is a chloride channel or a bicarbonate channel. In other preferred embodiments, the anion channel is a chloride channel.
  • the present invention provides a method of increasing the number of CFTR in a membrane of a cell, comprising the step of contacting said cell with a compound selected from Table 1.
  • a compound selected from Table 1 The term “functional CFTR” as used herein means CFTR that is capable of transport activity.
  • the activity of the CFTR is measured by measuring the transmembrane voltage potential.
  • Means for measuring the voltage potential across a membrane in the biological sample may employ any of the known methods in the art, such as optical membrane potential assay or other electrophysiological methods.
  • the optical membrane potential assay utilizes fluorescent voltage sensing dyes to measure changes in membrane potential using a fluorescent plate reader (e.g., FLIPR III, Molecular Devices, Inc.) as a readout for increase in functional ⁇ F508-CFTR in NIH 3T3 cells.
  • a fluorescent plate reader e.g., FLIPR III, Molecular Devices, Inc.
  • the driving force for the response is the creation of a chloride ion gradient in conjunction with channel activation by a single liquid addition step after the cells have previously been treated with compounds and subsequently loaded with a voltage sensing dye.
  • Voltage sensing dyes generally fall into three main categories.
  • the first is characterized by fast electro-chromic probes, such as Di-4-ANEPPS, that are capable of detecting microsecond voltage changes.
  • the second category are environment-sensitive dyes that distribute between cells and the extracellular solution as determined by the membrane potential.
  • the last category involves probes based on fluorescence resonance energy transfer measurements of rapid trans-membrane translocation of fluorescent hydrophobic ions (reference Gonzales, J. E., Worley, J and Van Goor, F. 2006. Ion Channel Assays Based on Ion and Voltage-Sensitive Fluorescent Probes. In Expression and Analysis of Recombinant Ion Channels. Edited by Jeffery J. Clare and Arthur J. Tresize. pp 187-211.)
  • the changes in fluorescence emission can be monitored using a variety of fluorescent plate readers which contain an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96-, 384- or 1536-well microtiter plates.
  • the present invention provides a kit for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo comprising (i) a composition comprising a compound selected from Table 1 or any of the above embodiments; and (ii) instructions for a) contacting the composition with the biological sample and b) measuring activity of said CFTR or a fragment thereof.
  • the kit further comprises instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound, and c) comparing the activity of the CFTR in the presence of the additional compound with the density of the CFTR in the presence of a composition selected from Table 1.
  • the assay utilizes fluorescent voltage sensing dyes to measure changes in membrane potential using a fluorescent plate reader (e.g., FLIPR III, Molecular Devices, Inc.) as a readout for increase in functional ⁇ F508-CFTR in NIH 3T3 cells.
  • a fluorescent plate reader e.g., FLIPR III, Molecular Devices, Inc.
  • the driving force for the response is the creation of a chloride ion gradient in conjunction with channel activation by a single liquid addition step after the cells have previously been treated with compounds and subsequently loaded with a voltage sensing dye.
  • the cells were incubated in serum-free medium for 16-24 hrs in tissue culture incubator at 37° C., 5% CO 2 , 90% humidity in the presence or absence (negative control) of test compound.
  • the cells were subsequently rinsed 3 ⁇ with Krebs Ringers solution and loaded with a voltage sensing redistribution dye.
  • 10 ⁇ M forskolin and the CFTR potentiator, genistein (20 ⁇ M) were added along with Cl ⁇ -free medium to each well.
  • the addition of Cl ⁇ -free medium promoted Cl ⁇ efflux in response to ⁇ F508-CFTR activation and the resulting membrane depolarization was optically monitored using voltage sensor dyes.
  • HTS assay utilizes fluorescent voltage sensing dyes to measure changes in membrane potential on the FLIPR III as a measurement for increase in gating (conductance) of ⁇ F508 CFTR in temperature-corrected ⁇ F508 CFTR NIH 3T3 cells.
  • the driving force for the response is a ion gradient in conjunction with channel activation with forskolin in a single liquid addition step using a fluoresecent plate reader such as FLIPR III after the cells have previously been treated with potentiator compounds (or DMSO vehicle control) and subsequently loaded with a redistribution dye.
  • Bath Solution #1 (in mM) NaCl 160, KCl 4.5, CaCl 2 2, MgCl 2 1, HEPES 10, pH 7.4 with NaOH.
  • Chloride-Free Bath Solution Chloride Salts in Bath Solution #1 are Substituted with Gluconate Salts.
  • NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for optical measurements of membrane potential.
  • the cells are maintained at 37° C. in 5% CO 2 and 90% humidity in Dulbccco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 ⁇ NEAA, ⁇ -ME, 1 ⁇ pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • the cells were seeded at 20,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37° C. before culturing at 27° C. for 24 hrs. for the potentiator assay.
  • the cells are cultured at 27° C. or 37° C. with and without compounds for 16-24 hours.
  • Non-CF and CF airway epithelia were isolated from bronchial tissue, cultured as previously described (Galietta, L. J. V., Lantero, S., Gazzolo, A., Sacco, O., Romano, L., Rossi, G. A., & Zegarra-Moran, O. (1998) In Vitro Cell. Dev. Biol. 34, 478-481), and plated onto Costar® SnapwellTM filters that were precoated with NIH3T3-conditioned media.
  • Non-CF HBE were isolated from non-smokers that did not have any known lung disease.
  • CF-HBE were isolated from patients homozygous for ⁇ F508-CFTR.
  • the basolateral solution contained (in mM) 145 NaCl, 0.83 K 2 HPO 4 , 3.3 KH 2 PO 4 , 1.2 MgCl 2 , 1.2 CaCl 2 , 10 Glucose, 10 HEPES (pH adjusted to 7.35 with NaOH) and the apical solution contained (in mM) 145 NaGluconate, 1.2 MgCl 2 , 1.2 CaCl 2 , 10 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH).
  • Typical protocol utilized a basolateral to apical membrane Cl concentration gradient. To set up this gradient, normal ringer was used on the basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl ⁇ concentration gradient across the epithelium. All experiments were performed with intact monolayers. To fully activate ⁇ F508-CFTR, forskolin (10 ⁇ M), PDE inhibitor, IBMX (100 ⁇ M) and CFTR potentiator, genistein (50 ⁇ M) were added to the apical side.
  • Typical protocol utilized a basolateral to apical membrane Cl concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large concentration gradient across the epithelium. Forskolin (10 ⁇ M) and all test compounds were added to the apical side of the cell culture inserts. The efficacy of the putative ⁇ F508-CFTR potentiators was compared to that of the known potentiator, genistein.
  • the pipette solution contained (in mM) 150 N-methyl-D-glucamine (NMDG)-Cl, 2 MgCl 2 , 2 CaCl 2 , 10 EGTA, 10 HEPES, and 240 ⁇ g/ml amphotericin-B (pH adjusted to 7.35 with HCl).
  • the extracellular medium contained (in mM) 150 NMDG-Cl, 2 MgCl 2 , 2 CaCl 2 , 10 HEPES (pH adjusted to 7.35 with HCl).
  • Pulse generation, data acquisition, and analysis were performed using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon Instruments Inc.). To activate ⁇ F508-CFTR, 10 ⁇ M forskolin and 20 ⁇ M genistein were added to the bath and the current-voltage relation was monitored every 30 sec.
  • the cells were incubated with 10 ⁇ M of the test compound for 24 hours at 37° C. and the current density was compared to the 27° C. and 37° C. controls (% activity). Prior to recording, the cells were washed 3 ⁇ with extracellular recording medium to remove any remaining test compound. Preincubation with 10 ⁇ M of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37° C. controls.
  • ⁇ F508-CFTR potentiators to increase the macroscopic ⁇ F508-CFTR Cl current (I ⁇ F508 ) in NIH3T3 cells stably expressing ⁇ F508-CFTR was also investigated using perforated-patch-recording techniques.
  • the potentiators identified from the optical assays evoked a dose-dependent increase in I ⁇ F508 with similar potency and efficacy observed in the optical assays.
  • the reversal potential before and during potentiator application was around ⁇ 30 mV, which is the calculated E Cl ( ⁇ 28 mV).
  • NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for whole-cell recordings.
  • the cells are maintained at 37° C. in 5% CO 2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 ⁇ NEAA, ⁇ -ME, 1 ⁇ pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • 2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27° C. before use to test the activity of potentiators; and incubated with or without the correction compound at 37° C. for measuring the activity of correctors.
  • the pipette contained (in mM): 150 NMDG, 150 aspartic acid, 5 CaCl 2 , 2 MgCl 2 , and 10 HEPES (pH adjusted to 7.35 with Tris base).
  • the bath contained (in mM): 150 NMDG-Cl, 2 MgCl 2 , 5 EGTA, 10 TES, and 14 Tris base (pH adjusted to 7.35 with HCl).
  • both wt- and ⁇ F508-CFTR were activated by adding 1 mM Mg-ATP, 75 nM of the catalytic subunit of cAMP-dependent protein kinase (PKA; Promega Corp.
  • PKA cAMP-dependent protein kinase
  • NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for excised-membrane patch-clamp recordings.
  • the cells are maintained at 37° C. in 5% CO 2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 ⁇ NEAA, 13-ME, 1 ⁇ pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • 2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27° C. before use.

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Abstract

The present invention relates to therapeutic combinations and kits useful in treating CFTR-related diseases, such as cystic fibrosis.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • The present application claims priority under 35 U.S.C. §119 to U.S. Provisional Application No. 60/954,850, filed Aug. 9, 2007 and entitled “THERAPEUTIC COMBINATIONS USEFUL IN TREATING CFTR RELATED DISEASES,” the entire contents of which is incorporated herein by reference.
    • TECHNICAL FIELD OF THE INVENTION
  • The present invention relates to therapeutic combinations and kits useful in treating CFTR-related diseases, such as cystic fibrosis.
    • BACKGROUND OF THE INVENTION
  • ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multidrug resistance proteins (like the MDR1-P glycoprotein, or the multidrug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function.
  • ABC transporters regulate a variety of important physiological roles within the body and provide defense against harmful environmental compounds. Because of this, they represent important potential drug targets for the treatment of diseases associated with defects in the transporter, prevention of drug transport out of the target cell, and intervention in other diseases in which modulation of ABC transporter activity may be beneficial.
  • One member of the ABC transporter family commonly associated with disease is the cAMP/ATP-mediated anion channel, CFTR. CFTR is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
  • The gene encoding CFTR has been identified and sequenced (See Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362), (Riordan, J. R. et al. (1989) Science 245:1066-1073). A defect in this gene causes mutations in CFTR resulting in cystic fibrosis (“CF”), the most common fatal genetic disease in humans. Cystic fibrosis affects approximately one in every 2,500 infants in the United States. Within the general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.
  • In patients with cystic fibrosis, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea—perhaps explaining the relatively high frequency of the CF gene within the population.
  • Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, >1000 disease causing mutations in the CF gene have been identified (http://www.genet.sickkids.on.cakftr/). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as ΔF508-CFTR. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.
  • The deletion of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies have shown, however, that the reduced numbers of ΔF508-CFTR in the membrane are functional, albeit less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to ΔF508-CFTR, other disease causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity.
  • Although CFTR transports a variety of molecules in addition to anions, it is clear that this role (the transport of anions) represents one element in an important mechanism of transporting ions and water across the epithelium. The other elements include the epithelial Na+ channel, ENaC, Na+/2Cl−K+ co-transporter, Na+—K+-ATPase pump and the basolateral membrane K+ channels, that are responsible for the uptake of chloride into the cell.
  • These elements work together to achieve directional transport across the epithelium via their selective expression and localization within the cell. Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na+—K+-ATPase pump and Cl− channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl− channels, resulting in a vectorial transport. Arrangement of Na+/2Cl−K+ co-transporter, Na+—K+ATPase pump and the basolateral membrane K+ channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.
  • In addition to cystic fibrosis, modulation of CFTR activity may be beneficial for other diseases not directly caused by mutations in CFTR, such as secretory diseases and other protein folding diseases mediated by CFTR. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjögren's Syndrome. COPD is characterized by airflow limitation that is progressive and not fully reversible. The airflow limitation is due to mucus hypersecretion, emphysema, and bronchiolitis. Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD. Specifically, increasing anion secretion across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and optimized periciliary fluid viscosity. This would lead to enhanced mucociliary clearance and a reduction in the symptoms associated with COPD. Dry eye disease is characterized by a decrease in tear aqueous production and abnormal tear film lipid, protein and mucin profiles. There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and diseases, such as cystic fibrosis and Sjögrens's syndrome. Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration. This would help to alleviate the symptoms associated with dry eye disease. Sjögrens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis. Defective protein trafficking is believed to cause the disease, for which treatment options are limited. Modulators of CFTR activity may hydrate the various organs afflicted by the disease and help to elevate the associated symptoms.
  • As discussed above, it is believed that the mutations in CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the ER, and traffic to the plasma membrane. As a result, insufficient amounts of the mature protein are present at the plasma membrane and chloride transport within epithelial tissues is significantly reduced. In fact, this cellular phenomenon of defective ER processing of ABC transporters by the ER machinery, has been shown to be the underlying basis not only for CF disease, but for a wide range of other isolated and inherited diseases. The two ways that the ER machinery can malfunction is either by loss of coupling to ER export of the proteins leading to degradation, or by the ER accumulation of these defective/misfolded proteins [Aridor M, et al., Nature Med., 5(7), pp 745-751 (1999); Shastry, B. S., et al., Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et al., Swiss Med Wkly, 132, pp 211-222 (2002); Morello, J P et al., TIPS, 21, pp. 466-469 (2000); Bross P., et al., Human Mut., 14, pp. 186-198 (1999)].
  • There are at least two known approaches to treat diseases such as cystic fibrosis caused by mutations in CFTR. In the first approach, the activity of residual mutated CFTR in the membrane is enhanced using modulators (“Potentiators”) that increase the gating activity of the mutated CFTR in the membrane. In another approach, the number of mutated CFTR in the membrane is increased using, thereby enhancing the CFTR activity in the membrane. This increase, or “Correction”, is believed to be the result of correcting the misfolding of the CFTR protein, which, in turn, would lead to enhanced trafficking to the membrane. Compounds that Correct such trafficking are called “Correctors”. Because of the complementary nature of these two approaches, a combination therapy employing these two approaches affords a potent method to treat diseases such as cystic fibrosis.
  • The diseases associated with the first class of ER malfunction are cystic fibrosis, hereditary emphysema (due to a1-antitrypsin; non Piz variants), hereditary hemochromatosis, hoagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, Mucopolysaccharidoses (due to lysosomal processing enzymes), Sandhof/Tay-Sachs (due to β-hexosaminidase), Crigler-Najjar type II (due to UDP-glucuronyl-sialyc-transferase), polyendocrinopathy/hyperinsulemia, Diabetes mellitus (due to insulin receptor), Laron dwarfism (due to growth hormone receptor), myleoperoxidase deficiency, primary hypoparathyroidism (due to preproparathyroid hormone), melanoma (due to tyrosinase). The diseases associated with the latter class of ER malfunction are Glycanosis CDG type 1, hereditary emphysema (due to α1-Antitrypsin (PiZ variant), congenital hyperthyroidism, osteogenesis imperfecta (due to Type I, II, IV procollagen), hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency (due to α1-antichymotrypsin), Diabetes insipidus (DI), neurophyseal DI (due to vasopvessin hormone/V2-receptor), neprogenic DI (due to aquaporin Charcot-Marie Tooth syndrome (due to peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to α APP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease (due to lysosomal β-galactosidase A) and Straussler-Scheinker syndrome (due to Prp processing defect).
  • In addition to up-regulation of CFTR activity, reducing anion secretion by CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport. The mechanism involves elevation of cAMP and stimulation of CFTR.
  • Although there are numerous causes of diarrhea, the major consequences of diarrheal diseases, resulting from excessive chloride transport are common to all, and include dehydration, acidosis, impaired growth and death.
  • Acute and chronic diarrheas represent a major medical problem in many areas of the world. Diarrhea is both a significant factor in malnutrition and the leading cause of death (5,000,000 deaths/year) in children less than five years old.
  • Secretory diarrheas are also a dangerous condition in patients of acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). 16 million travelers to developing countries from industrialized nations every year develop diarrhea, with the severity and number of cases of diarrhea varying depending on the country and area of travel.
  • Diarrhea in barn animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as scours, is a major cause of death in these animals. Diarrhea can result from any major transition, such as weaning or physical movement, as well as in response to a variety of bacterial or viral infections and generally occurs within the first few hours of the animal's life.
  • The most common diarrheal causing bacteria is enterotoxogenic E. coli (ETEC) having the K99 pilus antigen. Common viral causes of diarrhea include rotavirus and coronavirus. Other infectious agents include cryptosporidium, giardia lamblia, and salmonella, among others.
  • Symptoms of rotaviral infection include excretion of watery feces, dehydration and weakness. Coronavirus causes a more severe illness in the newborn animals, and has a higher mortality rate than rotaviral infection. Often, however, a young animal may be infected with more than one virus or with a combination of viral and bacterial microorganisms at one time. This dramatically increases the severity of the disease.
  • Accordingly, there is a need for a combination therapy to treat diseases such as cystic fibrosis using a Potentiators and a Corrector.
    • SUMMARY OF THE INVENTION
  • The present invention provides Corrector compounds pharmaceutically acceptable compositions thereof useful for treating or lessening the severity of a variety of CFTR-mediated diseases.
  • The present invention also provides therapeutic combinations of Correctors and Potentiators useful in treating CFTR-mediated diseases.
  • The present invention also provides therapeutic combinations of Correctors and Potentiators useful in treating diseases including, but not limited to, cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease.
    • DETAILED DESCRIPTION OF THE INVENTION I. General Description of Compounds of the Invention
  • The present invention relates to compounds that act as Correctors of CFTR and thus are useful in treating CFTR-mediated diseases.
  • The present invention also relates to combinations of Correctors of the present invention and a Potentiator. Exemplary Potentiators are disclosed below in Table 2; the compounds of Table 2 are previously in disclosed in WO 2006002421.
  • In one embodiment, the present invention relates to the use of Prazosin hydrochloride (1) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Prazosin hydrochloride and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient in need thereof. Prazosin hydrochloride and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Ivermectin (2) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Ivermectin and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Ivermectin and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Mibefradil hydrochloride (3) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Mibefradil hydrochloride and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Mibefradil hydrochloride and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Thioridazine (4) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Thioridazine and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Thioridazine and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Chlorpromazine hydrochloride (5) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Chlorpromazine hydrochloride and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Chlorpromazine hydrochloride and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Prochlorperazine maleate (6) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Prochlorperazine maleate and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Prochlorperazine maleate and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Perphenazine (7) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Perphenazine and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Perphenazine and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Amoxapine (8) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Amoxapine and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Amoxapine and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Clomiphene Citrate (9) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Clomiphene Citrate and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Clomiphene Citrate and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Amiodarone (10) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Amiodarone and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Amiodarone and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Desloratadine (11) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Desloratadine and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Desloratadine and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Promethazine hydrochloride (12) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Promethazine hydrochloride and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Promethazine hydrochloride and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Protriptyline hydrochloride (13) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Protriptyline hydrochloride and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Protriptyline hydrochloride and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Gefitinib (14) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Gefitinib and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Gefitinib and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Bepridil (15) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Bepridil and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Bepridil and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Itraconazole (16) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Itraconazole and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Itraconazole and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Oxyphenbutazone (17) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Oxyphenbutazone and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Oxyphenbutazone and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Clemastine fumarate (18) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Clemastine fumarate and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Clemastine fumarate and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Mefloquine Hydrochloride (19) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Mefloquine Hydrochloride and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Mefloquine Hydrochloride and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Thioguanine (20) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Thioguanine and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Thioguanine and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Paroxetine Hydrochloride Hemihydrate (21) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Paroxetine Hydrochloride Hemihydrate and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Paroxetine Hydrochloride Hemihydrate and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Vinpocetine (22) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Vinpocetine and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Vinpocetine and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Trimeprazine Tartrate (23) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Trimeprazine Tartrate and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Trimeprazine Tartrate and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Chlorimipramine hydrochloride (24) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Chlorimipramine hydrochloride and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Chlorimipramine hydrochloride and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Diphenoxylate Hydrochloride (25) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Diphenoxylate Hydrochloride and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Diphenoxylate Hydrochloride and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Amlodipine besylate (26) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Amlodipine besylate and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Amlodipine besylate and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Cyproheptadine hydrochloride (27) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Cyproheptadine hydrochloride and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Cyproheptadine hydrochloride and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Budesonide (28) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Budesonide and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Budesonide and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Ezetimibe (29) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Ezetimibe and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Ezetimibe and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Nitazoxanide (30) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Nitazoxanide and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Nitazoxanide and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Nelfinavir Mesylate (31) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Nelfinavir Mesylate and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Nelfinavir Mesylate and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Carvedilol (32) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Carvedilol and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Carvedilol and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Nortriptyline hydrochloride (33) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Nortriptyline hydrochloride and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Nortriptyline hydrochloride and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Loratadine (34) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Loratadine and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Loratadine and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Methylprednisolone (35) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Methylprednisolone and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Methylprednisolone and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Saquinavir (36) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Saquinavir and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Saquinavir and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Nicardipine hydrochloride (37) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Nicardipine hydrochloride and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Nicardipine hydrochloride and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Levothyroxine sodium (38) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Levothyroxine sodium and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Levothyroxine sodium and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Mirtazapine (39) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Mirtazapine and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Mirtazapine and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Cyclosporin A (40) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Cyclosporin A and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Cyclosporin A and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of Fluvastatin sodium (41) to correct the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising Fluvastatin sodium and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient Fluvastatin sodium and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
  • In one embodiment, the present invention relates to the use of 34542-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid (42) to modulate the activity of mutant CFTR. In another embodiment, the present invention provides a therapeutic combination comprising 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid and a compound selected from Table 2. In yet another embodiment, the present invention provides a method of treating a CFTR-mediated disease such as cystic fibrosis comprising the step of administering to a patient 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid and a compound selected from Table 2. In a preferred embodiment, said compound from Table 2 is compound 433.
    • 2. Compounds and Definitions
  • Exemplary Correctors of the present invention are set forth below in Table 1 below.
  • TABLE 1
    1
    Figure US20110177999A1-20110721-C00001
    2
    Figure US20110177999A1-20110721-C00002
    3
    Figure US20110177999A1-20110721-C00003
    4
    Figure US20110177999A1-20110721-C00004
    5
    Figure US20110177999A1-20110721-C00005
    6
    Figure US20110177999A1-20110721-C00006
    7
    Figure US20110177999A1-20110721-C00007
    8
    Figure US20110177999A1-20110721-C00008
    9
    Figure US20110177999A1-20110721-C00009
    10
    Figure US20110177999A1-20110721-C00010
    11
    Figure US20110177999A1-20110721-C00011
    12
    Figure US20110177999A1-20110721-C00012
    13
    Figure US20110177999A1-20110721-C00013
    14
    Figure US20110177999A1-20110721-C00014
    15
    Figure US20110177999A1-20110721-C00015
    16
    Figure US20110177999A1-20110721-C00016
    17
    Figure US20110177999A1-20110721-C00017
    18
    Figure US20110177999A1-20110721-C00018
    19
    Figure US20110177999A1-20110721-C00019
    20
    Figure US20110177999A1-20110721-C00020
    21
    Figure US20110177999A1-20110721-C00021
    22
    Figure US20110177999A1-20110721-C00022
    23
    Figure US20110177999A1-20110721-C00023
    24
    Figure US20110177999A1-20110721-C00024
    25
    Figure US20110177999A1-20110721-C00025
    26
    Figure US20110177999A1-20110721-C00026
    27
    Figure US20110177999A1-20110721-C00027
    28
    Figure US20110177999A1-20110721-C00028
    29
    Figure US20110177999A1-20110721-C00029
    30
    Figure US20110177999A1-20110721-C00030
    31
    Figure US20110177999A1-20110721-C00031
    32
    Figure US20110177999A1-20110721-C00032
    33
    Figure US20110177999A1-20110721-C00033
    34
    Figure US20110177999A1-20110721-C00034
    35
    Figure US20110177999A1-20110721-C00035
    36
    Figure US20110177999A1-20110721-C00036
    37
    Figure US20110177999A1-20110721-C00037
    38
    Figure US20110177999A1-20110721-C00038
    39
    Figure US20110177999A1-20110721-C00039
    40
    Figure US20110177999A1-20110721-C00040
    41
    Figure US20110177999A1-20110721-C00041
    42
    Figure US20110177999A1-20110721-C00042
  • The compounds of Table 1 are known drugs commercially marketed. One of skill in the art would be well aware of methods of making compounds of Table 1.
  • Exemplary Potentiators of the present invention are set forth below in Table 2 below.
  • TABLE 2
    Cmpd No. Name
    1 N-[5-(5-chloro-2-methoxy-phenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
    2 N-(3-methoxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    3 N-[2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    4 N-(2-morpholinophenyl)-4-oxo-1H-quinoline-3-carboxamide
    5 N-[4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    6 N-[3-(hydroxymethyl)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    7 N-(4-benzoylamino-2,5-diethoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    8 N-(3-amino-4-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    9 4-oxo-N-(3-sulfamoylphenyl)-1H-quinoline-3-carboxamide
    10 1,4-dihydro-N-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-4-oxoquinoline-3-carboxamide
    11 4-oxo-N-[2-[2-(trifluoromethyl)phenyl]phenyl]-1H-quinoline-3-carboxamide
    12 N-[2-(4-dimethylaminophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    13 N-(3-cyano-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    14 [5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-tert-butyl-phenyl]aminoformic acid methyl ester
    15 N-(2-methoxy-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    16 4-oxo-N-(2-propylphenyl)-1H-quinoline-3-carboxamide
    17 N-(5-amino-2-propoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    18 N-(9H-fluoren-1-yl)-4-oxo-1H-quinoline-3-carboxamide
    19 4-oxo-N-(2-quinolyl)-1H-quinoline-3-carboxamide
    20 N-[2-(2-methylphenoxy)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    21 4-oxo-N-[4-(2-pyridylsulfamoyl)phenyl]-1H-quinoline-3-carboxamide
    22 4-Oxo-1,4-dihydro-quinoline-3-carboxylic acid N-(1′,2′-dihydrospiro[cyclopropane-1,3′-[3H]indol]-6′-
    yl)-amide
    23 N-[2-(2-ethoxyphenyl)-5-hydroxy-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    24 4-oxo-N-(3-pyrrolidin-1-ylsulfonylphenyl)-1H-quinoline-3-carboxamide
    25 N-[2-(3-acetylaminophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    26 4-oxo-N-[2-(1-piperidyl)phenyl]-1H-quinoline-3-carboxamide
    27 N-[1-[2-[methyl-(2-methylaminoacetyl)-amino]acetyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-
    carboxamide
    28 [2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformic acid 2-
    methoxyethyl ester
    29 1-isopropyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide
    30 [2-isopropyl-5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformic acid methyl ester
    31 4-oxo-N-(p-tolyl)-1H-quinoline-3-carboxamide
    32 N-(5-chloro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    33 N-(1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    34 N-[4-(1,1-diethylpropyl)-2-fluoro-5-hydroxy-phenyl]-4-hydroxy-quinoline-3-carboxamide
    35 1,4-dihydro-N-(2,3,4,5-tetrahydro-5,5-dimethyl-1H-benzo[b]azepin-8-yl)-4-oxoquinoline-3-carboxamide
    36 N-(2-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    37 N-(1H-indol-7-yl)-4-oxo-1H-quinoline-3-carboxamide
    38 N-[2-(1H-indol-2-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    39 [3-[(2,4-dimethoxy-3-quinolyl)carbonylamino]-4-tert-butyl-phenyl]aminoformic acid tert-butyl ester
    40 N-[2-(2-hydroxyethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    41 N-(5-amino-2-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    42 N-[2-[[3-chloro-5-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-4-oxo-1H-quinoline-3-carboxamide
    43 N-[2-(3-ethoxyphenyl)-5-hydroxy-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    44 N-(2-methylbenzothiazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
    45 N-(2-cyano-3-fluoro-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    46 N-[3-chloro-5-(2-morpholinoethylsulfonylamino)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    47 N-[4-isopropyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    48 N-(5-chloro-2-fluoro-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    49 N-[2-(2,6-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    50 4-oxo-N-(2,4,6-trimethylphenyl)-1H-quinoline-3-carboxamide
    51 6-[(4-methyl-1-piperidyl)sulfonyl]-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
    52 N-[2-(m-tolyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    53 4-oxo-N-(4-pyridyl)-1H-quinoline-3-carboxamide
    54 4-oxo-N-(8-thia-7,9-diazabicyclo[4.3.0]nona-2,4,6,9-tetraen-5-yl)-1H-quinoline-3-carboxamide
    55 N-(3-amino-2-methoxy-5-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    56 1,4-dihydro-N-(1,2,3,4-tetrahydro-6-hydroxynaphthalen-7-yl)-4-oxoquinoline-3-carboxamide
    57 N-[4-(3-ethyl-2,6-dioxo-3-piperidyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    58 N-[3-amino-4-(trifluoromethoxy)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    59 N-[2-(5-isopropyl-2-methoxy-phenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    60 [4-isopropyl-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformic acid tert-butyl ester
    61 N-(2,3-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    62 4-oxo-N-[3-(trifluoromethoxy)phenyl]-1H-quinoline-3-carboxamide
    63 N-[2-(2,4-difluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    64 4-oxo-N-(2-oxo-1,3-dihydrobenzoimidazol-5-yl)-1H-quinoline-3-carboxamide
    65 4-oxo-N-[5-(3-pyridyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide
    66 N-(2,2-difluorobenzo[1,3]dioxol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
    67 6-ethyl-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
    68 3-[2-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]benzoic acid methyl ester
    69 N-(3-amino-4-isopropyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    70 4-oxo-N-[2-(4-pyridyl)phenyl]-1H-quinoline-3-carboxamide
    71 3-[2-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]benzoic acid isopropyl ester
    72 N-(2-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    73 4-oxo-N-(2-phenyl-3H-benzoimidazol-5-yl)-1H-quinoline-3-carboxamide
    74 4-oxo-N-[5-(trifluoromethyl)-2-pyridyl]-1H-quinoline-3-carboxamide
    75 4-oxo-N-(3-quinolyl)-1H-quinoline-3-carboxamide
    76 N-[2-(3,4-difluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    77 N-(5-fluoro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    78 4-oxo-N-(2-sulfamoylphenyl)-1H-quinoline-3-carboxamide
    79 N-[2-(4-fluoro-3-methyl-phenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    80 N-(2-methoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
    81 4-oxo-N-(3-propionylaminophenyl)-1H-quinoline-3-carboxamide
    82 N-(4-diethylamino-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    83 N-[2-(3-cyanophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    84 N-(4-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    85 N-[2-(3,4-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    86 N-[4-[2-(aminomethyl)phenyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide
    87 4-oxo-N-(3-phenoxyphenyl)-1H-quinoline-3-carboxamide
    88 [2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformic acid tert-butyl
    ester
    89 N-(2-cyano-5-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    90 4-oxo-N-(2-tert-butylphenyl)-1H-quinoline-3-carboxamide
    91 N-(3-chloro-2,6-diethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    92 N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    93 N-[2-(5-cyano-2-thienyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    94 N-(5-amino-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    95 N-(2-cyanophenyl)-4-oxo-1H-quinoline-3-carboxamide
    96 N-[3-(cyanomethyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
    97 N-[2-(2,4-dimethoxypyrimidin-5-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    98 N-(5-dimethylamino-2-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    99 4-oxo-N-(4-pentylphenyl)-1H-quinoline-3-carboxamide
    100 N-(1H-indol-4-yl)-4-oxo-1H-quinoline-3-carboxamide
    101 N-(5-amino-2-isopropyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    102 N-[2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]phenyl]-4-oxo-1H-quinoline-3-carboxamide
    103 6-fluoro-N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    104 N-(2-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    105 1,4-dihydro-N-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-oxoquinoline-3-carboxamide
    106 N-(2-cyano-4,5-dimethoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    107 7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl
    ester
    108 4,4-dimethyl-7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-1-carboxylic acid
    tert-butyl ester
    109 N-(1-acetyl-2,3,4,5-tetrahydro-5,5-dimethyl-1H-benzo[b]azepin-8-yl)-1,4-dihydro-4-oxoquinoline-3-
    carboxamide
    110 N-[4-(cyanomethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    111 4-oxo-N-[2-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide
    112 6-ethoxy-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
    113 N-(3-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    114 [4-(2-ethoxyphenyl)-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformic acid tert-butyl ester
    115 N-[2-(2-furyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    116 5-hydroxy-N-(1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    117 N-(3-dimethylamino-4-isopropyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    118 N-[2-(1H-indol-5-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    119 [2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformic acid ethyl ester
    120 N-(2-methoxy-5-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    121 N-(3,4-dichlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
    122 N-(3,4-dimethoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
    123 N-[2-(3-furyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    124 6-fluoro-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
    125 N-(6-ethyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    126 N-[3-hydroxy-4-[2-(2-methoxyethoxy)-1,1-dimethyl-ethyl]-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    127 [5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-tert-butyl-phenyl]aminoformic acid ethyl ester
    128 1,6-dimethyl-4-oxo-N-(2-phenylphenyl)-1H-quinoline-3-carboxamide
    129 [2-ethyl-5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformic acid methyl ester
    130 4-hydroxy-N-(1H-indol-6-yl)-5,7-bis(trifluoromethyl)quinoline-3-carboxamide
    131 N-(3-amino-5-chloro-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    132 N-(5-acetylamino-2-ethoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    133 N-[3-chloro-5-[2-(1-piperidyl)ethylsulfonylamino]phenyl]-4-oxo-1H-quinoline-3-carboxamide
    134 N-[2-(4-methylsulfinylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    135 N-(2-benzo[1,3]dioxol-5-ylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    136 N-(2-hydroxy-3,5-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    137 6-[(4-fluorophenyl)-methyl-sulfamoyl]-N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-
    carboxamide
    138 N-[2-(3,5-difluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    139 N-[2-(2,4-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    140 N-(4-cyclohexylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    141 [2-methyl-5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformic acid ethyl ester
    142 4-oxo-N-(2-sec-butylphenyl)-1H-quinoline-3-carboxamide
    143 N-(2-fluoro-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    144 N-(3-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
    145 6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-4-carboxylic acid ethyl ester
    146 4-oxo-N-(1,7,9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-5-yl)-1H-quinoline-3-carboxamide
    147 N-[2-(4-fluorophenoxy)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide
    148 4-oxo-N-[5-(1-piperidylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide
    149 N-(3-acetylamino-4-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    150 4-oxo-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-1H-quinoline-3-carboxamide
    151 N-[2-(4-methyl-2-thienyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    152 4-oxo-N-(2-oxo-3H-benzooxazol-6-yl)-1H-quinoline-3-carboxamide
    153 N-[4-(1,1-diethyl-2,2-dimethyl-propyl)-2-fluoro-5-hydroxy-phenyl]-4-hydroxy-quinoline-3-carboxamide
    154 N-[3,5-bis(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    155 4-oxo-N-(2-pyridyl)-1H-quinoline-3-carboxamide
    156 4-oxo-N-[2-[2-(trifluoromethoxy)phenyl]phenyl]-1H-quinoline-3-carboxamide
    157 N-(2-ethyl-5-methylamino-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    158 4-oxo-N-(5-phenyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
    159 [7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acid methyl ester
    160 N-(3-amino-4-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    161 N-[3-(2-ethoxyethoxy)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    162 N-(6-methoxy-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    163 N-[5-(aminomethyl)-2-(2-ethoxyphenyl)-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    164 4-oxo-N-[3-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide
    165 4-oxo-N-(4-sulfamoylphenyl)-1H-quinoline-3-carboxamide
    166 4-[2-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]benzoic acid methyl ester
    167 N-(3-amino-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    168 4-oxo-N-(3-pyridyl)-1H-quinoline-3-carboxamide
    169 N-(1-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    170 N-(5-chloro-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    171 N-[2-(2,3-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    172 N-(2-(benzo[b]thiophen-2-yl)phenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide
    173 N-(6-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    174 N-[2-(5-acetyl-2-thienyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    175 4-Oxo-1,4-dihydro-quinoline-3-carboxylic acid N-(1′-Acetyl-1′,2′-dihydrospiro[cyclopropane-1,3′-3H-
    indol]-6′-yl)-amide
    176 4-oxo-N-[4-(trifluoromethoxy)phenyl]-1H-quinoline-3-carboxamide
    177 N-(2-butoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
    178 4-oxo-N-[2-(2-tert-butylphenoxy)phenyl]-1H-quinoline-3-carboxamide
    179 N-(3-carbamoylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    180 N-(2-ethyl-6-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    181 4-oxo-N-[2-(p-tolyl)phenyl]-1H-quinoline-3-carboxamide
    182 N-[2-(4-fluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    183 7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-1-carboxylic acid tert-butyl ester
    184 N-(1H-indol-6-yl)-4-oxo-2-(trifluoromethyl)-1H-quinoline-3-carboxamide
    185 N-(3-morpholinosulfonylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    186 N-(3-cyclopentyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    187 N-(1-acetyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    188 6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acid ethyl ester
    189 N-(4-benzyloxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
    190 N-[2-(3-chloro-4-fluoro-phenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    191 4-oxo-N-(5-quinolyl)-1H-quinoline-3-carboxamide
    192 N-(3-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    193 N-(2,6-dimethoxy-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    194 N-(4-cyanophenyl)-4-oxo-1H-quinoline-3-carboxamide
    195 N-(5-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    196 N-[5-(3,3-dimethylbutanoylamino)-2-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    197 4-oxo-N-[6-(trifluoromethyl)-3-pyridyl]-1H-quinoline-3-carboxamide
    198 N-(4-fluorophenyl)-4-oxo-1H-quinoline-3-carboxamide
    199 N-[2-(o-tolyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    200 1,4-dihydro-N-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-oxoquinoline-3-carboxamide
    201 N-(2-cyano-3-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    202 N-[2-(5-chloro-2-methoxy-phenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    203 N-(1-benzyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    204 N-(4,4-dimethylchroman-7-yl)-4-oxo-1H-quinoline-3-carboxamide
    205 N-[2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    206 N-[2-(2,3-dimethylphenoxy)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide
    207 2-[6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indol-3-yl]acetic acid ethyl ester
    208 N-[4-(2-adamantyl)-5-hydroxy-2-methyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    209 N-[4-(hydroxymethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    210 2,4-dimethoxy-N-(2-phenylphenyl)-quinoline-3-carboxamide
    211 N-(2-methoxy-5-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    212 N-[3-(3-methyl-5-oxo-1,4-dihydropyrazol-1-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    213 N-[2-(2,5-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    214 N-(3-methylsulfonylaminophenyl)-4-oxo-1H-quinoline-3-carboxamide
    215 4-oxo-N-phenyl-1H-quinoline-3-carboxamide
    216 N-(3H-benzoimidazol-2-yl)-4-oxo-1H-quinoline-3-carboxamide
    217 N-(1H-indazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
    218 6-fluoro-N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    219 4-oxo-N-pyrazin-2-yl-1H-quinoline-3-carboxamide
    220 N-(2,3-dihydroxy-4,6-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    221 [5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-propyl-phenyl]aminoformic acid methyl ester
    222 N-(3-chloro-2-cyano-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    223 N-[2-(4-methylsulfanylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    224 4-oxo-N-[4-[2-[(2,2,2-trifluoroacetyl)aminomethyl]phenyl]phenyl]-1H-quinoline-3-carboxamide
    225 [2-isopropyl-5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformic acid ethyl ester
    226 4-oxo-N-(4-propylphenyl)-1H-quinoline-3-carboxamide
    227 N-[2-(3H-benzoimidazol-2-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    228 N-[2-(hydroxy-phenyl-methyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    229 N-(2-methylsulfanylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    230 N-(2-methyl-1H-indol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
    231 3-[4-hydroxy-2-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-5-tert-butyl-phenyl]benzoic acid methyl ester
    232 N-(5-acetylamino-2-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    233 N-(1-acetylindolin-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    234 4-oxo-N-[5-(trifluoromethyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide
    235 N-(6-isopropyl-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    236 4-oxo-N-[4-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide
    237 N-[5-(2-methoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
    238 7′-[(4-oxo-1H-quinolin-3-ylcarbonyl)amino]-spiro[piperidine-4,4′(1′H)-quinoline], 2′,3′-dihydro-
    carboxylic acid tert-butyl ester
    239 [4-isopropyl-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformic acid methyl ester
    240 N-(2-benzyloxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
    241 4-oxo-N-(8-quinolyl)-1H-quinoline-3-carboxamide
    242 N-(5-amino-2,4-dichloro-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    243 N-(5-acetylamino-2-isopropyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    244 4-oxo-N-(6,7,8,9-tetrahydro-5H-carbazol-2-yl)-1H-quinoline-3-carboxamide
    245 N-[2-(2,4-dichlorophenoxy)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    246 N-(3,4-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    247 4-oxo-N-[2-(2-phenoxyphenyl)phenyl]-1H-quinoline-3-carboxamide
    248 N-(3-acetylamino-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    249 [4-ethyl-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformic acid methyl ester
    250 N-(5-acetylamino-2-methoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    251 [2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformic acid isobutyl ester
    252 N-(2-benzoylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    253 4-oxo-N-[2-[3-(trifluoromethoxy)phenyl]phenyl]-1H-quinoline-3-carboxamide
    254 6-fluoro-N-(5-fluoro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    255 N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-6-pyrrolidin-1-ylsulfonyl-1H-quinoline-3-carboxamide
    256 N-(1H-benzotriazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
    257 N-(4-fluoro-3-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    258 N-indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide
    259 4-oxo-N-(3-sec-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
    260 N-(5-amino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    261 N-[2-(3,4-dimethylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    262 1,4-dihydro-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]thiazin-6-yl)-4-oxoquinoline-3-carboxamide
    263 N-(4-bromo-2-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    264 N-(2,5-diethoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
    265 N-(2-benzylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    266 N-[5-hydroxy-4-tert-butyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    267 4-oxo-N-(4-phenoxyphenyl)-1H-quinoline-3-carboxamide
    268 4-oxo-N-(3-sulfamoyl-4-tert-butyl-phenyl)-1H-quinoline-3-carboxamide
    269 [4-isopropyl-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformic acid ethyl ester
    270 N-(2-cyano-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    271 N-(3-amino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    272 N-[3-(2-morpholinoethylsulfonylamino)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    273 [7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acid tert-butyl ester
    274 4-oxo-6-pyrrolidin-1-ylsulfonyl-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
    275 4-benzyloxy-N-(3-hydroxy-4-tert-butyl-phenyl)-quinoline-3-carboxamide
    276 N-(4-morpholinosulfonylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    277 N-[2-(3-fluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    278 4-oxo-N-[2-[3-(trifluoromethyl)phenyl]phenyl]-1H-quinoline-3-carboxamide
    279 N-[2-(2-methylsulfanylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    280 4-oxo-N-(6-quinolyl)-1H-quinoline-3-carboxamide
    281 N-(2,4-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    282 N-(5-amino-2-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    283 N-[2-(3-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    284 N-(1H-indazol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    285 N-[2-(2,3-difluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    286 1,4-dihydro-N-(1,2,3,4-tetrahydronaphthalen-5-yl)-4-oxoquinoline-3-carboxamide
    287 N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)-phenyl]-5-hydroxy-4-oxo-1H-quinoline-3-carboxamide
    288 N-(5-fluoro-2-methoxycarbonyloxy-3-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    289 N-(2-fluoro-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    290 N-[2-(3-isopropylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    291 N-(2-chloro-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    292 N-(5-chloro-2-phenoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    293 4-oxo-N-[2-(1H-pyrrol-1-yl)phenyl]-1H-quinoline-3-carboxamide
    294 N-(1H-indol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
    295 4-oxo-N-(2-pyrrolidin-1-ylphenyl)-1H-quinoline-3-carboxamide
    296 2,4-dimethoxy-N-(2-tert-butylphenyl)-quinoline-3-carboxamide
    297 N-[2-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    298 [2-ethyl-5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformic acid ethyl ester
    299 4-oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-quinoline-3-carboxamide
    300 N-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide
    301 N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    302 N-[2-[4-(hydroxymethyl)phenyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide
    303 N-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide
    304 [4-(2-ethoxyphenyl)-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenylmethyl]aminoformic acid tert-
    butyl ester
    305 N-[2-(4-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    306 N-[2-(3-ethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    307 N-[2-(3-chlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    308 N-[2-(cyanomethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    309 N-(3-isoquinolyl)-4-oxo-1H-quinoline-3-carboxamide
    310 4-oxo-N-(4-sec-butylphenyl)-1H-quinoline-3-carboxamide
    311 N-[2-(5-methyl-2-furyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    312 N-[2-(2,4-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    313 N-[2-(2-fluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    314 N-(2-ethyl-6-isopropyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    315 N-(2,6-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    316 N-(5-acetylamino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    317 N-(2,6-dichlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
    318 4-oxo-N-[3-[2-(1-piperidyl)ethylsulfonylamino]-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide
    319 6-fluoro-N-(2-fluoro-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    320 4-oxo-N-(2-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
    321 N-[2-(4-benzoylpiperazin-1-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    322 N-(2-ethyl-6-sec-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    323 [2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformic acid methyl ester
    324 N-(4-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    325 N-(2,6-diethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    326 N-[2-(4-methylsulfonylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    327 N-[5-(2-ethoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
    328 N-(3-acetylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    329 N-[2-(o-tolyl)benzooxazol-5-yl]-4-oxo-1H-quinoline-3-carboxamide
    330 N-(2-chlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
    331 N-(2-carbamoylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    332 N-(4-ethynylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    333 N-[2-[4-(cyanomethyl)phenyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide
    334 7′-[(4-oxo-1H-quinolin-3-ylcarbonyl)amino]-spiro[piperidine-4,4′(1′H)-1-acetyl-quinoline], 2′,3′-dihydro-
    carboxylic acid tert-butyl ester
    335 N-(2-carbamoyl-5-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    336 N-(2-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    337 N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide
    338 N-(3-methyl-1H-indol-4-yl)-4-oxo-1H-quinoline-3-carboxamide
    339 N-(3-cyano-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    340 N-(3-methylsulfonylamino-4-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    341 [2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformic acid neopentyl
    ester
    342 N-[5-(4-isopropylphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
    343 N-[5-(isobutylcarbamoyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
    344 N-[2-(2-ethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    345 6-fluoro-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
    346 4-oxo-N-phenyl-7-(trifluoromethyl)-1H-quinoline-3-carboxamide
    347 N-[5-[4-(2-dimethylaminoethylcarbamoyl)phenyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
    348 N-[2-(4-ethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    349 4-oxo-N-(2-phenylsulfonylphenyl)-1H-quinoline-3-carboxamide
    350 N-(1-naphthyl)-4-oxo-1H-quinoline-3-carboxamide
    351 N-(5-ethyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    352 2-[6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indol-3-yl]ethylaminoformic acid tert-butyl ester
    353 [3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-4-tert-butyl-phenyl]aminoformic acid tert-butyl ester
    354 N-[2-[(cyclohexyl-methyl-amino)methyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide
    355 N-[2-(2-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    356 N-(5-methylamino-2-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    357 N-(3-isopropyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    358 6-chloro-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
    359 N-[3-(2-dimethylaminoethylsulfonylamino)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-
    carboxamide
    360 N-[4-(difluoromethoxy)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    361 N-[2-(2,5-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    362 N-(2-chloro-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    363 N-[2-(2-fluoro-3-methoxy-phenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    364 N-(2-methyl-8-quinolyl)-4-oxo-1H-quinoline-3-carboxamide
    365 N-(2-acetylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    366 4-oxo-N-[2-[4-(trifluoromethyl)phenyl]phenyl]-1H-quinoline-3-carboxamide
    367 N-[2-(3,5-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    368 N-(3-amino-4-propoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    369 N-(2,4-dichloro-6-cyano-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    370 N-(3-chlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
    371 4-oxo-N-[2-(trifluoromethylsulfanyl)phenyl]-1H-quinoline-3-carboxamide
    372 N-[2-(4-methyl-1-piperidyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    373 N-indan-4-yl-4-oxo-1H-quinoline-3-carboxamide
    374 4-hydroxy-N-(1H-indol-6-yl)-2-methylsulfanyl-quinoline-3-carboxamide
    375 1,4-dihydro-N-(1,2,3,4-tetrahydronaphthalen-6-yl)-4-oxoquinoline-3-carboxamide
    376 4-oxo-N-(2-phenylbenzooxazol-5-yl)-1H-quinoline-3-carboxamide
    377 6,8-difluoro-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
    378 N-(3-amino-4-methoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    379 N-[3-acetylamino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    380 N-(2-ethoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
    381 4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
    382 [5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-propyl-phenyl]aminoformic acid ethyl ester
    383 N-(3-ethyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    384 N-[2-(2,5-difluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    385 N-[2-(2,4-difluorophenoxy)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide
    386 N-(3,3-dimethylindolin-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    387 N-[2-methyl-3-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    388 4-oxo-N-[2-[4-(trifluoromethoxy)phenyl]phenyl]-1H-quinoline-3-carboxamide
    389 N-(3-benzylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    390 N-[3-(aminomethyl)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    391 N-[2-(4-isobutylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    392 N-(6-chloro-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    393 N-[5-amino-2-(2-ethoxyphenyl)-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    394 1,6-dimethyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide
    395 N-[4-(1-adamantyl)-2-fluoro-5-hydroxy-phenyl]-4-hydroxy-quinoline-3-carboxamide
    396 [2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformic acid
    tetrahydrofuran-3-ylmethyl ester
    397 4-oxo-N-(4-phenylphenyl)-1H-quinoline-3-carboxamide
    398 4-oxo-N-[2-(p-tolylsulfonylamino)phenyl]-1H-quinoline-3-carboxamide
    399 N-(2-isopropyl-5-methylamino-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    400 N-(6-morpholino-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    401 N-[2-(2,3-dimethylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    402 4-oxo-N-(5-phenyl-2-pyridyl)-1H-quinoline-3-carboxamide
    403 N-[2-fluoro-5-hydroxy-4-(1-methylcyclooctyl)-phenyl]-4-hydroxy-quinoline-3-carboxamide
    404 N-[5-(2,6-dimethoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
    405 N-(4-chlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
    406 6-[(4-fluorophenyl)-methyl-sulfamoyl]-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-
    carboxamide
    407 N-(2-fluoro-5-hydroxy-4-tert-butyl-phenyl)-5-hydroxy-4-oxo-1H-quinoline-3-carboxamide
    408 N-(3-methoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
    409 N-(5-dimethylamino-2-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    410 4-oxo-N-[2-(4-phenoxyphenyl)phenyl]-1H-quinoline-3-carboxamide
    411 7-chloro-4-oxo-N-phenyl-1H-quinoline-3-carboxamide
    412 6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-7-carboxylic acid ethyl ester
    413 4-oxo-N-(2-phenoxyphenyl)-1H-quinoline-3-carboxamide
    414 N-(3H-benzoimidazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
    415 N-(3-hydroxy-4-tert-butyl-phenyl)-4-methoxy-quinoline-3-carboxamide
    416 [2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformic acid propyl ester
    417 N-(2-(benzo[b]thiophen-3-yl)phenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide
    418 N-(3-dimethylaminophenyl)-4-oxo-1H-quinoline-3-carboxamide
    419 N-(3-acetylaminophenyl)-4-oxo-1H-quinoline-3-carboxamide
    420 2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propanoic acid ethyl ester
    421 N-[5-methoxy-4-tert-butyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    422 N-(5,6-dimethyl-3H-benzoimidazol-2-yl)-4-oxo-1H-quinoline-3-carboxamide
    423 N-[3-(2-ethoxyethyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
    424 N-[2-(4-chlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    425 N-(4-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    426 N-(4-chloro-5-hydroxy-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    427 5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl
    ester
    428 N-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    429 N-[3-amino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    430 N-(2-isopropyl-6-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    431 N-(3-aminophenyl)-4-oxo-1H-quinoline-3-carboxamide
    432 N-[2-(4-isopropylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    433 N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    434 N-(2,5-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    435 N-[2-(2-fluorophenoxy)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide
    436 N-[2-(3,4-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    437 N-benzo[1,3]dioxol-5-yl-4-oxo-1H-quinoline-3-carboxamide
    438 N-[5-(difluoromethyl)-2,4-ditert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    439 N-(4-methoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
    440 N-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,4-dihydro-4-oxoquinoline-3-carboxamide
    441 N-[3-methylsulfonylamino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    442 4-oxo-N-[3-(1-piperidylsulfonyl)phenyl]-1H-quinoline-3-carboxamide
    443 4-oxo-N-quinoxalin-6-yl-1H-quinoline-3-carboxamide
    444 5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-tert-butyl-benzoic acid methyl ester
    445 N-(2-isopropenylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    446 N-(1,1-dioxobenzothiophen-6-yl)-4-oxo-1H-quinoline-3-carboxamide
    447 N-(3-cyanophenyl)-4-oxo-1H-quinoline-3-carboxamide
    448 4-oxo-N-(4-tert-butylphenyl)-1H-quinoline-3-carboxamide
    449 N-(m-tolyl)-4-oxo-1H-quinoline-3-carboxamide
    450 N-[4-(1-hydroxyethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    451 N-(4-cyano-2-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    452 4-oxo-N-(4-vinylphenyl)-1H-quinoline-3-carboxamide
    453 N-(3-amino-4-chloro-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    454 N-(2-methyl-5-phenyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    455 N-[4-(1-adamantyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
    456 4-oxo-N-[3-(trifluoromethylsulfanyl)phenyl]-1H-quinoline-3-carboxamide
    457 N-(4-morpholinophenyl)-4-oxo-1H-quinoline-3-carboxamide
    458 N-[3-(2-hydroxyethoxy)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide
    459 N-(o-tolyl)-4-oxo-1H-quinoline-3-carboxamide
    460 [2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformic acid butyl ester
    461 4-oxo-N-(2-phenylphenyl)-1H-quinoline-3-carboxamide
    462 N-(3-dimethylamino-4-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    463 N-(4-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    464 5-hydroxy-N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    465 [5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-tert-butyl-phenylmethyl]aminoformic acid tert-butyl ester
    466 N-(2,6-diisopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide
    467 N-(2,3-dihydrobenzofuran-5-yl)-4-oxo-1H-quinoline-3-carboxamide
    468 1-methyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide
    469 4-oxo-N-(2-phenylphenyl)-7-(trifluoromethyl)-1H-quinoline-3-carboxamide
    470 4-oxo-N-(4-phenylsulfanylphenyl)-1H-quinoline-3-carboxamide
    471 [3-[(4-oxo-1H-quinoline-3-yl)carbonylamino]-4-propyl-phenyl]aminoformic acid methyl ester
    472 [4-ethyl-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformic acid ethyl ester
    473 1-isopropyl-4-oxo-N-(2-tert-butylphenyl)-1H-quinoline-3-carboxamide
    474 N-(3-methyl-2-oxo-3H-benzooxazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
    475 N-(2,5-dichloro-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    476 N-(2-cyano-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    477 N-(5-fluoro-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
    478 4-oxo-N-(3-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
    479 N-(1H-indol-6-yl)-5-methoxy-4-oxo-1H-quinoline-3-carboxamide
    480 1-ethyl-6-methoxy-4-oxo-N-phenyl-1H-quinoline-3-carboxamide
    481 N-(2-naphthyl)-4-oxo-1H-quinoline-3-carboxamide
    482 [7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acid ethyl ester
    483 N-[2-fluoro-5-hydroxy-4-(1-methylcycloheptyl)-phenyl]-4-hydroxy-quinoline-3-carboxamide
    484 N-(3-methylamino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
    485 N-(3-dimethylamino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide
  • The compounds of Table 2, and methods of making and use the same, are disclosed in WO 2006002421, the entire disclosure being incorporated herein by reference.
  • As used herein, the term “therapeutic combination” means a combination of two or more therapeutic compounds either (i) administered to a patient in need thereof simultaneously in separate formulations or in a single formulation; or (ii) administered to a patient in need thereof at different timepoints as part of a regimen.
  • As used herein, the term “CFTR-mediated disases” means a disease selected from cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysacchari doses, Sandhof/Tay-Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease.
  • 5. Uses, Formulation and Administration
  • Pharmaceutically Acceptable Compositions
  • As discussed above, the present invention provides compounds that are useful as modulators of CFTR and thus are useful in the treatment of disease, disorders or conditions such as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease.
  • Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
  • It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative or a prodrug thereof. According to the present invention, a pharmaceutically acceptable derivative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • Uses of Compounds and Pharmaceutically Acceptable Compositions
  • In yet another aspect, the present invention provides a method of treating a condition, disease, or disorder implicated by ABC transporter activity, e.g., CFTR. In certain embodiments, the present invention provides a method of treating a condition, disease, or disorder implicated by a deficiency of the ABC transporter activity, the method comprising administering a composition comprising a compound selected from Table 1 to a subject, preferably a mammal, in need thereof.
  • In certain embodiments, the present invention provides a method of treating cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease, comprising the step of administering to said mammal an effective amount of a composition comprising a compound of the present invention.
  • According to an alternative preferred embodiment, the present invention provides a method of treating cystic fibrosis comprising the step of administering to said patient a composition comprising a compound of the present invention.
  • According to the invention an “effective amount” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoprotenemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease.
  • The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease.
  • In one embodiment, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in a patient.
  • In certain embodiments, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia. The presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary Cl− concentrations, or ex vivo biochemical or histochemical techniques to monitor cell surface density. Using such methods, residual CFTR activity can be readily detected in patients heterozygous or homozygous for a variety of different mutations, including patients homozygous or heterozygous for the most common mutation, □F508.
  • In another embodiment, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients who have residual CFTR activity induced or augmented using pharmacological methods or gene therapy. Such methods increase the amount of CFTR present at the cell surface, thereby inducing a hitherto absent CFTR activity in a patient or augmenting the existing level of residual CFTR activity in a patient.
  • In one embodiment, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients within certain genotypes exhibiting residual CFTR activity, e.g., class III mutations (impaired regulation or gating), class IV mutations (altered conductance), or class V mutations (reduced synthesis) (Lee R. Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV, and V cystic fibrosis Tansmembrane Conductance Regulator Defects and Opportunities of Therapy; Current Opinion in Pulmonary Medicine 6:521-529, 2000). Other patient genotypes that exhibit residual CFTR activity include patients homozygous for one of these classes or heterozygous with any other class of mutations, including class I mutations, class II mutations, or a mutation that lacks classification.
  • In one embodiment, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients within certain clinical phenotypes, e.g., a moderate to mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia. Such phenotypes include patients exhibiting pancreatic sufficiency or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease.
  • The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.
  • The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microcmulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
  • The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • As described generally above, the compounds of the invention are useful as modulators of CFTR. Thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of CFTR is implicated in the disease, condition, or disorder. When hyperactivity or inactivity of an ABC transporter is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “ABC transporter-mediated disease, condition or disorder”. Accordingly, in another aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of an ABC transporter is implicated in the disease state.
  • The activity of a compound utilized in this invention as a modulator of an ABC transporter may be assayed according to methods described generally in the art and in the Examples herein.
  • It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated”.
  • In one embodiment, the additional agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound of the present invention, or a nutritional agent.
  • The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • In another embodiment, the present invention provides a kit comprising:
      • a. a pharmaceutical composition comprising a compound selected from Table 1;
      • b. a pharmaceutical composition comprising a compound selected from Table 2; and
      • c. instructions for using said kit for treating cystic fibrosis.
  • In one embodiment, said compound selected from Table 2 is compound 433.
  • In another embodiment, said instructions in said kit comprises instructions for using said pharmaceutical composition comprising a compound selected from Table 1 and said pharmaceutical composition comprising a compound selected from Table 2.
  • Another aspect of the invention relates to modulating CFTR activity in a biological sample or a patient (e.g., in vitro or in vivo), which method comprises administering to the patient, or contacting said biological sample with a compound selected from Table 1 or a composition comprising said compound. The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Modulation of CFTR in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of ABC transporters in biological and pathological phenomena; and the comparative evaluation of new modulators of CFTR.
  • In yet another embodiment, a method of modulating activity of an anion channel in vitro or in vivo, is provided comprising the step of contacting said channel with a compound selected from Table 1. In preferred embodiments, the anion channel is a chloride channel or a bicarbonate channel. In other preferred embodiments, the anion channel is a chloride channel.
  • According to an alternative embodiment, the present invention provides a method of increasing the number of CFTR in a membrane of a cell, comprising the step of contacting said cell with a compound selected from Table 1. The term “functional CFTR” as used herein means CFTR that is capable of transport activity.
  • According to another preferred embodiment, the activity of the CFTR is measured by measuring the transmembrane voltage potential. Means for measuring the voltage potential across a membrane in the biological sample may employ any of the known methods in the art, such as optical membrane potential assay or other electrophysiological methods.
  • The optical membrane potential assay utilizes fluorescent voltage sensing dyes to measure changes in membrane potential using a fluorescent plate reader (e.g., FLIPR III, Molecular Devices, Inc.) as a readout for increase in functional ΔF508-CFTR in NIH 3T3 cells. The driving force for the response is the creation of a chloride ion gradient in conjunction with channel activation by a single liquid addition step after the cells have previously been treated with compounds and subsequently loaded with a voltage sensing dye.
  • Voltage sensing dyes generally fall into three main categories. The first is characterized by fast electro-chromic probes, such as Di-4-ANEPPS, that are capable of detecting microsecond voltage changes. The second category are environment-sensitive dyes that distribute between cells and the extracellular solution as determined by the membrane potential. The last category involves probes based on fluorescence resonance energy transfer measurements of rapid trans-membrane translocation of fluorescent hydrophobic ions (reference Gonzales, J. E., Worley, J and Van Goor, F. 2006. Ion Channel Assays Based on Ion and Voltage-Sensitive Fluorescent Probes. In Expression and Analysis of Recombinant Ion Channels. Edited by Jeffery J. Clare and Derek J. Tresize. pp 187-211.) The changes in fluorescence emission can be monitored using a variety of fluorescent plate readers which contain an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96-, 384- or 1536-well microtiter plates.
  • In another aspect the present invention provides a kit for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo comprising (i) a composition comprising a compound selected from Table 1 or any of the above embodiments; and (ii) instructions for a) contacting the composition with the biological sample and b) measuring activity of said CFTR or a fragment thereof. In one embodiment, the kit further comprises instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound, and c) comparing the activity of the CFTR in the presence of the additional compound with the density of the CFTR in the presence of a composition selected from Table 1.
  • In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
    • EXAMPLES Assays for Detecting and Measuring ΔF508-CFTR Correction Properties of Compounds
  • Membrane Potential Optical Methods for Assaying ΔF508-CFTR Modulation Properties of Compounds
  • The assay utilizes fluorescent voltage sensing dyes to measure changes in membrane potential using a fluorescent plate reader (e.g., FLIPR III, Molecular Devices, Inc.) as a readout for increase in functional ΔF508-CFTR in NIH 3T3 cells. The driving force for the response is the creation of a chloride ion gradient in conjunction with channel activation by a single liquid addition step after the cells have previously been treated with compounds and subsequently loaded with a voltage sensing dye.
  • Identification of Correction Compounds
  • To identify small molecules that correct the trafficking defect associated with ΔF508-CFTR; a single-addition HTS assay format was developed. Assay Plates containing cells are incubated for ˜2-4 hours in tissue culture incubator at 37° C., 5% CO2, 90% humidity. Cells are then ready for compound exposure after adhering to the bottom of the assay plates.
  • The cells were incubated in serum-free medium for 16-24 hrs in tissue culture incubator at 37° C., 5% CO2, 90% humidity in the presence or absence (negative control) of test compound. The cells were subsequently rinsed 3× with Krebs Ringers solution and loaded with a voltage sensing redistribution dye. To activate ΔF508-CFTR, 10 μM forskolin and the CFTR potentiator, genistein (20 μM), were added along with Cl−-free medium to each well. The addition of Cl−-free medium promoted Cl− efflux in response to ΔF508-CFTR activation and the resulting membrane depolarization was optically monitored using voltage sensor dyes.
  • Identification of Potentiator Compounds
  • To identify potentiators of ΔF508-CFTR, a double-addition HTS assay format was developed. This HTS assay utilizes fluorescent voltage sensing dyes to measure changes in membrane potential on the FLIPR III as a measurement for increase in gating (conductance) of ΔF508 CFTR in temperature-corrected ΔF508 CFTR NIH 3T3 cells. The driving force for the response is a ion gradient in conjunction with channel activation with forskolin in a single liquid addition step using a fluoresecent plate reader such as FLIPR III after the cells have previously been treated with potentiator compounds (or DMSO vehicle control) and subsequently loaded with a redistribution dye.
    • Solutions:
  • Bath Solution #1: (in mM) NaCl 160, KCl 4.5, CaCl2 2, MgCl2 1, HEPES 10, pH 7.4 with NaOH.
  • Chloride-Free Bath Solution: Chloride Salts in Bath Solution #1 are Substituted with Gluconate Salts.
  • Cell Culture
  • NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for optical measurements of membrane potential. The cells are maintained at 37° C. in 5% CO2 and 90% humidity in Dulbccco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME, 1× pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For all optical assays, the cells were seeded at 20,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37° C. before culturing at 27° C. for 24 hrs. for the potentiator assay. For the correction assays, the cells are cultured at 27° C. or 37° C. with and without compounds for 16-24 hours. Electrophysiological Assays for assaying ΔF508-CFTR modulation properties of compounds.
  • 1. Using Chamber Assay
  • Using chamber experiments were performed on polarized airway epithelial cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulators identified in the optical assays. Non-CF and CF airway epithelia were isolated from bronchial tissue, cultured as previously described (Galietta, L. J. V., Lantero, S., Gazzolo, A., Sacco, O., Romano, L., Rossi, G. A., & Zegarra-Moran, O. (1998) In Vitro Cell. Dev. Biol. 34, 478-481), and plated onto Costar® Snapwell™ filters that were precoated with NIH3T3-conditioned media. After four days the apical media was removed and the cells were grown at an air liquid interface for >14 days prior to use. This resulted in a monolayer of fully differentiated columnar cells that were ciliated, features that are characteristic of airway epithelia. Non-CF HBE were isolated from non-smokers that did not have any known lung disease. CF-HBE were isolated from patients homozygous for ΔF508-CFTR.
  • HBE grown on Costar® Snapwell™ cell culture inserts were mounted in an Ussing chamber (Physiologic Instruments, Inc., San Diego, Calif.), and the transepithelial resistance and short-circuit current in the presence of a basolateral to apical CC gradient (ISC) were measured using a voltage-clamp system (Department of Bioengineering, University of Iowa, Iowa). Briefly, HBE were examined under voltage-clamp recording conditions (Vhold=0 mV) at 37° C. The basolateral solution contained (in mM) 145 NaCl, 0.83 K2HPO4, 3.3 KH2PO4, 1.2 MgCl2, 1.2 CaCl2, 10 Glucose, 10 HEPES (pH adjusted to 7.35 with NaOH) and the apical solution contained (in mM) 145 NaGluconate, 1.2 MgCl2, 1.2 CaCl2, 10 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH).
  • Identification of Correction Compounds
  • Typical protocol utilized a basolateral to apical membrane Cl concentration gradient. To set up this gradient, normal ringer was used on the basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl− concentration gradient across the epithelium. All experiments were performed with intact monolayers. To fully activate ΔF508-CFTR, forskolin (10 μM), PDE inhibitor, IBMX (100 μM) and CFTR potentiator, genistein (50 μM) were added to the apical side.
  • As observed in other cell types, incubation at low temperatures of FRT cells and human bronchial epithelial cells isolated from diseased CF patients (CF-HBE)expressing ΔF508-CFTR increases the functional density of CFTR in the plasma membrane. To determine the activity of correction compounds, the cells were incubated with test compound for 24-48 hours at 37° C. and were subsequently washed 3× prior to recording. The cAMP-and genistein-mediated ISC in compound-treated cells was normalized to 37° C. controls and expressed as percentage activity of CFTR activity in wt-HBE. Preincubation of the cells with the correction compound significantly increased the cAMP- and genistein-mediated ISC compared to the 37° C. controls.
  • Identification of Potentiator Compounds
  • Typical protocol utilized a basolateral to apical membrane Cl concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large concentration gradient across the epithelium. Forskolin (10 μM) and all test compounds were added to the apical side of the cell culture inserts. The efficacy of the putative ΔF508-CFTR potentiators was compared to that of the known potentiator, genistein.
  • 2. Patch-Clamp Recordings
  • Total Cl− current in ΔF508-NIH3T3 cells was monitored using the perforated-patch recording configuration as previously described (Rae, J., Cooper, K., Gates, P., & Watsky, M. (1991). J. Neurosci. Methods 37, 15-26). Voltage-clamp recordings were performed at 22° C. using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, Calif.). The pipette solution contained (in mM) 150 N-methyl-D-glucamine (NMDG)-Cl, 2 MgCl2, 2 CaCl2, 10 EGTA, 10 HEPES, and 240 μg/ml amphotericin-B (pH adjusted to 7.35 with HCl). The extracellular medium contained (in mM) 150 NMDG-Cl, 2 MgCl2, 2 CaCl2, 10 HEPES (pH adjusted to 7.35 with HCl). Pulse generation, data acquisition, and analysis were performed using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon Instruments Inc.). To activate ΔF508-CFTR, 10 μM forskolin and 20 μM genistein were added to the bath and the current-voltage relation was monitored every 30 sec.
  • Identification of Correction Compounds
  • To determine the activity of correction compounds for increasing the density of functional ΔF508-CFTR in the plasma membrane, we used the above-described perforated-patch-recording techniques to measure the current density following 24-hr treatment with the correction compounds. To fully activate ΔF508-CFTR, 10 μM forskolin and 20 μM genistein were added to the cells. Under our recording conditions, the current density following 24-hr incubation at 27° C. was higher than that observed following 24-hr incubation at 37° C. These results are consistent with the known effects of low-temperature incubation on the density of ΔF508-CFTR in the plasma membrane. To determine the effects of correction compounds on CFTR current density, the cells were incubated with 10 μM of the test compound for 24 hours at 37° C. and the current density was compared to the 27° C. and 37° C. controls (% activity). Prior to recording, the cells were washed 3× with extracellular recording medium to remove any remaining test compound. Preincubation with 10 μM of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37° C. controls.
  • Identification of Potentiator Compounds
  • The ability of ΔF508-CFTR potentiators to increase the macroscopic ΔF508-CFTR Cl current (IΔF508) in NIH3T3 cells stably expressing ΔF508-CFTR was also investigated using perforated-patch-recording techniques. The potentiators identified from the optical assays evoked a dose-dependent increase in IΔF508 with similar potency and efficacy observed in the optical assays. In all cells examined, the reversal potential before and during potentiator application was around −30 mV, which is the calculated ECl (−28 mV).
  • Cell Culture
  • NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for whole-cell recordings. The cells are maintained at 37° C. in 5% CO2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME, 1× pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For whole-cell recordings, 2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27° C. before use to test the activity of potentiators; and incubated with or without the correction compound at 37° C. for measuring the activity of correctors.
  • 3. Single-Channel Recordings
  • Gating activity of wt-CFTR and temperature-corrected ΔF508-CFTR expressed in NIH3T3 cells was observed using excised inside-out membrane patch recordings as previously described (Dalemans, W., Barbry, P., Champigny, G., Jallat, S., Doti, K., Dreyer, D., Crystal, R. G., Pavirani, A., Lecocq, J-P., Lazdunski, M. (1991) Nature 354, 526-528) using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). The pipette contained (in mM): 150 NMDG, 150 aspartic acid, 5 CaCl2, 2 MgCl2, and 10 HEPES (pH adjusted to 7.35 with Tris base). The bath contained (in mM): 150 NMDG-Cl, 2 MgCl2, 5 EGTA, 10 TES, and 14 Tris base (pH adjusted to 7.35 with HCl). After excision, both wt- and ΔF508-CFTR were activated by adding 1 mM Mg-ATP, 75 nM of the catalytic subunit of cAMP-dependent protein kinase (PKA; Promega Corp. Madison, Wis.), and 10 mM NaF to inhibit protein phosphatases, which prevented current rundown. The pipette potential was maintained at 80 mV. Channel activity was analyzed from membrane patches containing 2 active channels. The maximum number of simultaneous openings determined the number of active channels during the course of an experiment. To determine the single-channel current amplitude, the data recorded from 120 sec of ΔF508-CFTR activity was filtered “off-line” at 100 Hz and then used to construct all-point amplitude histograms that were fitted with multigaussian functions using Bio-Patch Analysis software (Bio-Logic Comp. France). The total microscopic current and open probability (Po) were determined from 120 sec of channel activity. The Po was determined using the Bio-Patch software or from the relationship Po I/i(N), where I=mean current, i=single-channel current amplitude, and N=number of active channels in patch.
  • Cell Culture
  • NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for excised-membrane patch-clamp recordings. The cells are maintained at 37° C. in 5% CO2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, 13-ME, 1× pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For single channel recordings, 2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27° C. before use.
  • The compounds of Table 1 were found to exhibit Correction activity as measured in the assay described above.
  • The compounds of Table 2 were found to exhibit Potentiation activity as measured in the assay described above.

Claims (15)

1. A method of treating cystic fibrosis in a patient comprising the step of administering to said patient a compound selected from Table 1.
2. The method of claim 1, further comprising the step of administering to said patient a compound selected from Table 2.
3. The method according to claim 2, wherein said compound is compound 433.
4. A pharmaceutical composition comprising:
a. a compound selected from Table 1;
b. a compound selected from Table 2; and
c. a pharmaceutically suitable excipient.
5. The pharmaceutical composition according to claim 4, wherein said compound from Table 2 is compound 433.
6. A therapeutic combination comprising a compound selected from Table 1 and a compound selected from Table 2.
7. The therapeutic combination according to claim 6, wherein said compound from Table 2 is compound 433.
8. A kit comprising:
a. a pharmaceutical composition comprising a compound selected from Table 1;
b. a pharmaceutical composition comprising a compound selected from Table 2; and
c. instructions for using said kit for treating cystic fibrosis.
9. A method of correcting the activity of mutant CFTR in a cell, comprising the step of contacting said cell with a compound selected from Table 1.
10. A method of enhancing the activity of mutant CFTR in a cell, comprising the step of contacting said cell with a compound selected from Table 1 and a compound selected from Table 2.
11. The method according to claim 9, wherein said cell is ex-vivo.
12. The method according to claim 9, wherein said cell is in-vivo.
13. The method according to claim 10, wherein said compound selected from Table 2 is compound 433.
14. The method according to claim 10, wherein said cell is ex-vivo.
15. The method according to claim 10, wherein said cell is in-vivo.
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Cited By (42)

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Publication number Priority date Publication date Assignee Title
US20080306062A1 (en) * 2005-11-08 2008-12-11 Hadida Ruah Sara S Modulators of atp-binding cassette transporters
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US20090176839A1 (en) * 2007-12-07 2009-07-09 Ali Keshavarz-Shokri Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US20090253736A1 (en) * 2007-11-02 2009-10-08 Vertex Pharmaceuticals Incorporated Azaindole derivatives as cftr modulators
US20100036130A1 (en) * 2007-12-07 2010-02-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US20100087490A1 (en) * 2008-09-29 2010-04-08 Vertex Pharmaceuticals Incorporated Dosage Units of 3-(6-(1-(2,2-Difluorobenzo[D] [1,3] Dioxol-5-YL) Cyclopropanecarboxamido)-3-Methylpyridin-2-YL)Benzoic Acid
US20100113508A1 (en) * 2008-10-23 2010-05-06 Vertex Pharmaceuticals, Incorporated Modulators of Cystic Fibrosis Transmembrane Conductance Regulator
US20100113555A1 (en) * 2006-04-07 2010-05-06 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette Transporters
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US10653678B2 (en) 2016-04-11 2020-05-19 Genfit Methods of treatment for cholestatic and fibrotic diseases
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EP3466934B1 (en) * 2016-05-31 2024-03-27 Taiho Pharmaceutical Co., Ltd. Sulfonamide compounds or salt thereof as ribonucleotide reductase inhibitors for treating cancer
JP2020514352A (en) * 2017-03-13 2020-05-21 ジェンフィＧｅｎｆｉｔ Pharmaceutical composition for combination therapy
WO2019028456A1 (en) * 2017-08-04 2019-02-07 Axial Biotherapeutics, Inc. Inhibitors of microbially induced amyloid

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8354427B2 (en) * 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ587551A (en) * 2004-06-24 2012-01-12 Vertex Pharma 5-Amino-phenol derivatives such as 5-amino-2,4-di-tert-butyl-phenol
KR20070114820A (en) * 2005-03-18 2007-12-04 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 Compounds having activity in correcting mutant-cftr processing and uses thereof
WO2008089135A2 (en) * 2007-01-12 2008-07-24 University Of South Florida Identification of biomarkers predictive of dasatinib effects in cancer cells

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8354427B2 (en) * 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Foley & Tilley, Quinoline Antimalarials: Mechanisms of Action and Resistance and Prospects for New Agents, 79(1) PHARMACOL. THER. 55-87 (1998) *
Haren et al., The effects of the inhaled corticosteroid budesonide on lung function and bronchial hyperresponsiveness in adult patients with cystic fibrosis, 89 RESP. MED. 209-214 (1995) *

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US20100113508A1 (en) * 2008-10-23 2010-05-06 Vertex Pharmaceuticals, Incorporated Modulators of Cystic Fibrosis Transmembrane Conductance Regulator
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US20150099781A1 (en) * 2009-03-20 2015-04-09 Brandeis University Compounds and Methods for Treating Mammalian Gastrointestinal Microbial Infections
US10125116B2 (en) * 2009-03-20 2018-11-13 Brandeis University Compounds and methods for treating mammalian gastrointestinal microbial infections
US11578062B2 (en) 2010-03-25 2023-02-14 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
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WO2014086687A1 (en) 2012-12-03 2014-06-12 Universita' Degli Studi Di Padova A cftr corrector for the teatment of genetic disorders affecting striated muscle
US10231932B2 (en) 2013-11-12 2019-03-19 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
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WO2016196297A1 (en) * 2015-05-29 2016-12-08 Emory University 2-amino-n'-benzylideneacetohydrazides and derivatives for the management of cftr protein mediated diseases
CN105330602A (en) * 2015-12-07 2016-02-17 江南大学 Decoquinate analogue and application thereof
JP2019513761A (en) * 2016-04-11 2019-05-30 ジェンフィＧｅｎｆｉｔ Method of treating cholestatic and fibrotic diseases
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KR20180129934A (en) * 2016-04-11 2018-12-05 장피트 Methods for the treatment of cholestatic and fibrotic diseases
KR102431257B1 (en) * 2016-04-11 2022-08-10 장피트 Methods of treatment of cholestatic and fibrotic diseases
EP3777854A1 (en) * 2016-04-11 2021-02-17 Genfit Methods of treatment for cholestatic and fibrotic diseases

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